1. Field of the Invention
The invention relates generally to measurement of blood and tissue analytes. More particularly the invention relates to a method of screening for disorders of glucose metabolism.
2. Background Information
Diabetes is a chronic and incurable disease in which the body does not produce or properly use insulin, a hormone that allows glucose to enter the cells of the body and be utilized for energy. The cause of diabetes is not yet known, although both genetic and environmental factors such as obesity and lack of exercise appear to play roles. People with diabetes have increased risk of cardiovascular disease as well as retinopathy and neuropathy. It has been shown that tight control of glucose levels in the diabetic population to normoglycemic or slightly hyperglycemic levels results in delayed onset and slowed progression of retinopathy, nephropathy, and neuropathy [See DCCT study group, The New England Journal of Medicine, 341:1306:1309 (1993)].
With inadequate insulin utilization, glucose builds in the bloodstream instead of transporting into cells. The body is unable to use glucose for energy despite the increasing levels of glucose circulating in the blood. Initial glucose elevations may cause no symptoms. Later, the elevations may cause symptoms of fatigue, excessive thirst, urination, and hunger. These symptoms are non-descript and are often not reported to health care providers. Many people have unknown elevations for years without proper management of the disease because current diagnostic test procedures were either not ordered or not opportune during the health care visit.
There are three major types of diabetes:
Type I—Insulin Dependent Diabetes Mellitus (IDDM)—Also known as Juvenile-Onset Diabetes
Type I diabetes is an autoimmune disease in which the body's own immune system destroys the pancreatic cells which produce insulin. This disease can occur at any age, but most often occurs in people under thirty years of age. Type I diabetes accounts for approximately ten percent of all diabetics. Presentation of symptoms is usually severe and develops rapidly. People with this condition require daily doses of insulin to stay alive. Although the exact cause of Type I diabetes is unknown, genetics, viruses that injure the pancreas, and destruction of insulin-making cells by the body's immune system may play causative roles.
Type II—Non-insulin Dependent Diabetes Mellitus (NIDDM)—Also known as Adult-Onset Diabetes
Type II diabetes usually occurs due to a metabolic disorder known as insulin resistance, an inability to properly use insulin combined with relative insulin deficiency. This form of diabetes is the most common form of diabetes, accounting for approximately ninety percent of cases. People in the following categories are at a higher risk of developing Type II diabetes:                Over age forty-five;        Family history of diabetes;        Overweight;        Lack of regular exercise;        Low HDL cholesterol        High triglycerides;        Certain racial and ethnic groups; and        Women who have had gestational diabetes.Gestational Diabetes        
According to the American Diabetes Association, Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy, whether or not the condition persists after pregnanoy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy.
Risk assessment for GDM should be undertaken at the first prenatal visit with testing undertaken at 24-28 weeks of gestation for those at high risk:                Age >25 years;        Overweight or obese;        Member of an ethnic group with a high prevalence of GDM;        Family history of diabetes;        History of stillbirth or high birth weight infants; or        Previous gestational diabetes.Diabetes Prevalence and Trends        
Approximately seven percent of all pregnancies are complicated by GDM, resulting in more than two hundred thousand cases annually. The prevalence may range from one to fourteen percent of all pregnancies, depending on the population studied and the diagnostic tests employed.
The World Health Organization estimates that diabetes currently afflicts one hundred fifty-four million people worldwide, fifty-four million of who live in developed countries. They also predict that the number of people with diabetes worldwide will grow to three hundred million by 2025.
As many as 15.7 million Americans, or 5.9% of the population, have diabetes with approximately 5.4 million of these people being undiagnosed. The number of Americans with diabetes has recently been estimated to be growing at a rate of nine percent per year.
In the United States, the prevalence of adults with diagnosed diabetes increased by six percent in 1999 and rose thirty-three percent nationally between 1990 and 1998. There are approximately eight hundred thousand new cases every year in America.
The risk for Type II diabetes increases with age. An estimated eighteen percent of the American population aged sixty-five and older has diabetes.
In addition to millions of Americans who suffer from diabetes, it is estimated that an additional twenty to thirty million Americans suffer from Impaired Glucose Tolerance (IGT). Approximately twenty-five percent of the American population aged sixty-five and older suffer from IGT.
Impaired Glucose Tolerence
It is estimated that eleven percent of the American public has this condition. Impaired glucose tolerance may be viewed as an intermediate condition between normal glucose metabolism and type II diabetes. Impaired glucose tolerance is a condition in which blood sugar levels are higher than normal, but do not meet the diagnostic criteria for diabetes. Persons with IGT have a five-fold risk of developing diabetes within five years. However, the Diabetes Prevention Study has shown that early detection and intervention may delay or prevent the onset of diabetes. It also has recently been discovered that IGT individuals are at higher risk for cardiovascular disease and death, a risk evaluated in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policeman Study [See Diabetes Care, 21:360-367 (1998)] and discovered to be greater than in people with diabetes. It is reasonable to suppose that with the early detection and treatment of IGT, strategies to mitigate cardiovascular risk as well as diabetes prevention may be pursued. Prevention or early treatment of diabetes would have the added benefit of reducing diabetic complications such as kidney disease, nerve disease, blindness, diabetic ketoacidosis, and a shorter lifespan. For these reason, early detection of IGT is critical to the general health of our population.
Hyperinsulinemia (Postprandial Reactive Hypoglycemia)
Postprandial reactive hypoglycemia is a medical condition in which symptoms occur after a meal as a response to food stimulation as opposed to a fasting state. Blood sugar levels are normally around 90 to 110 mg/dL, but with hypoglycemia they are usually below 50 mg/dL and may get as low as 35 mg/dL.
There are two reasons for the symptoms: 1) adrenaline release and 2) glucose deprivation of the nervous system. Low blood sugar stimulates the release of adrenaline, which causes shakiness, sweating, hunger pangs, nervousness, and irritability. The brain doesn't get enough sugar, and commonly reported symptoms are headache, mental dullness, and fatigue. If the blood sugar drops too low, a person can get confused, have visual problems, develop a seizure, or even become unconscious.
It is theorized that the cause of the abnormal response stems from first phase vs. second phase insulin release mechanisms in the pancreas. First phase release is diminished allowing a rapid increase in blood glucose levels. It is followed by an over-responsive second phase release causing a dramatic drop in glucose to hypoglycemic levels. Some people with reactive hypoglycemia go on to develop diabetes.
Adverse Clinical Effects of Diabetes and Impaired Glucose Tolerence
Diabetes and impaired glucose tolerance have been called “silent killers” because many people are unaware that they have the disease until they develop one of its life-threatening complications. Complications of diabetes include retinopathy, neuropathy, and cardiovascular problems.
Heart Disease and Stroke: People with diabetes are two to four times more likely to have heart disease or suffer a stroke. Additionally, heart disease is present in seventy-five percent of diabetes-related deaths.
Kidney Disease: Long-term hyperglycemia results in the kidneys filtering excess blood. This extra work results in small leaks. Protein is lost into the urine. A small amount of protein in the urine is microalbuminuria while a larger concentration is proteinuria or macroalbuminuria. The overwork also diminishes the filtering capacity of the kidneys, ultimately leading to end-stage renal disease. While not everyone who has diabetes develops kidney disease, diabetes is the leading cause of end-stage renal disease, accounting for about forty percent of new cases each year. Between ten and twenty percent of all diabetics develop kidney disease due to diabetic nephropathy and require dialysis or a kidney transplant in order to stay alive.
Neuropathy (Nerve Disease and Amputations): A common complication of diabetes is diabetic neuropathy, which is a group of nerve diseases affecting peripheral nerves especially those of the fingertips and toes. Roughly two-thirds of diabetics have some form of neuropathy with symptoms ranging from loss of sensation in the feet to lower limb amputation due to unnoticed infections. Each year, fifty-six thousand Americans lose a lower limb to diabetes.
Retinopathy: Retinopathy includes all abnormalities of the small blood vessels of the retina caused by diabetes. Most diabetics have nothing more than minor eye disorders related to their diabetes. However, diabetes is the leading cause of new cases of blindness among those aged twenty to seventy-four years with twelve thousand to twenty-four thousand new blindness cases due to diabetic retinopathy occurring each year. Overall, people with diabetes have a higher risk of blindness. Early detection and treatment of diabetes can reduce the risk of blindness in many patients.
Diabetic Ketoacidosis (DKA): One of the most serious outcomes of poorly controlled diabetes, DKA is marked by high blood glucose levels along with ketones in the urine and occurs primarily in Type I individuals. DKA is responsible for about ten percent of diabetes-related deaths in individuals under age forty-five.
Skin Conditions: Diabetes may also affect the skin. Up to one third of diabetics may have a skin disorder during some part of their life. Skin problems that occur primarily with diabetics are dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive xanthomatosis.
Gum Disease: There is an increased risk in diabetics of developing periodontal disease. Excess circulatory glucose contributes to bacterial plaque formation.
Shorter Lifespan: Life expectancy of people with diabetes averages fifteen years less than people without the disease. Diabetes is the seventh leading cause of death in the United States, contributing to approximately two hundred thousand deaths per year.
Impotence: Males are more likely to experience impotence due to changes or disturbances in the peripheral nervous system (neuropathy) or blood vessel blockage. Impotence affects approximately thirteen percent of men with Type I diabetes and eight percent of men with Type II diabetes.
Fetal Complications: Infants of gestationally diabetic mothers are at higher risk of fetal anomalies, e.g. birth defects, macrosomia, higher birth weights, post-partum hypoglycemia, and respiratory distress syndrome.
In view of the above, there exists a great need in the art for a rapid, convenient, and economical method for routine and early detection of disorders of glucose metabolism.